A major problem in drug design is how to avoid side effects due to non specific reactivity as well as cross reactivity with closely related target receptors and receptor subtypes. In this regard,conotoxins are of particular interest. They are produced by venomous cone snails that prey, for example, on fish. The disparity in the mobility of predator and prey makes it absolutely imperative that the snail's toxins act rapidly. This means that once injected into the prey, a toxin molecule must be very focused, and not 'distracted' on the way to its target. In other words, the toxin must act with high selectivity. Furthermore, the snail is limited in the amount of venom it can deliver, so the toxin must act with high avidity as well. Cone snails have had 50 million years to evolve what we now have come to appreciate are incredibly efficient drugs. In this project, we hope to unlock the secret of the how cone snails produce toxins with such highly desirable pharmacological attributes. Among the constituents of cone venom are a large family of peptides, the alpha-conotoxins, which interact with the nicotinic acetylcholine receptor (nAChR) with a remarkably high degree of selectivity. This proposal explores the structural features which confer upon alpha- conotoxins their pharmacologically attractive features. This will be done by systematically altering their structures and examining the functional consequence. It is anticipated that this study will provide new information on drug-target interactions which will assist in the design of more efficacious drugs.